1. Field of the Invention
The field of this invention is the treatment of neurodegenerative disorders using stem cells. More specifically, the HUCB cell is administered to the individual in need of treatment along with a substance that permeabilizes the blood brain barrier in order to enhance the neuroprotective effect of the stem cells.
2. Background Art
Cerebrovascular disease, considered one of the top five non-communicable diseases, affects approximately 50 million people worldwide, resulting in approximately 5.5 million deaths per year. Of those 50 million, stroke accounts for roughly 40 million people. Stroke is the third leading cause of death in developed countries and accounts for the major cause of adult disability.
Stroke treatment consists of two categories: prevention and acute management. Prevention treatments currently consist of antiplatelet agents, anticoagulation agents, surgical therapy, angioplasty, lifestyle adjustments, and medical adjustments. An antiplatelet agent commonly used is aspirin. The use of anticoagulation agents seems to have no statistical significance. Surgical therapy appears to be effective for specific sub-groups. Angioplasty is still an experimental procedure with insufficient data for analysis. Lifestyle adjustments include quitting smoking, regular exercise, regulation of eating, limiting sodium intake, and moderating alcohol consumption. Medical adjustments include medications to lower blood pressure, lowering cholesterol, controlling diabetes, and controlling circulation problems.
Acute management treatments consist of the use of thrombolytics, neuroprotective agents, Oxygenated Fluorocarbon Nutrient Emulsion (OFNE) Therapy, Neuroperfusion, GPIIb/IIIa Platelet Inhibitor Therapy, and Rehabilitation/Physical Therapy.
A thrombolytic agent induces or moderates thrombolysis, and the most commonly used agent is tissue plasminogen activator (t-PA). Recombinant t-PA (rt-PA) helps reestablish cerebral circulation by dissolving (lysing) the clots that obstruct blood flow. It is an effective treatment, with an extremely short therapeutic window; it must be administered within 3 hours from onset. It also requires a CT scan prior to administration of the treatment, further reducing the amount of time available. Genetech Pharmaceuticals manufactures ACTIVASE® and is currently the only source of rt-PA.
Neuroprotective agents are drugs that minimize the effects of the ischemic cascade, and include, for example, Glutamate Antagonists, Calcium Antagonists, Opiate Antagonists, GABA-A Agonists, Calpain Inhibitors, Kinase Inhibitors, and Antioxidants. Several different clinical trials for acute ischemic stroke are in progress. Due to their complementary functions of clot-busting and brain-protection, future acute treatment procedures will most likely involve the combination of thrombolytic and neuroprotective therapies. However, like thrombolytics, most neuroprotectives need to be administered within 6 hours after a stroke to be effective.
Oxygenated Fluorocarbon Nutrient Emulsion (OFNE) Therapy delivers oxygen and nutrients to the brain through the cerebral spinal fluid. Neuroperfusion is an experimental procedure in which oxygen-rich blood is rerouted through the brain as a way to minimize the damage of an ischemic stroke. GPIIb/IIIa Platelet Inhibitor Therapy inhibits the ability of the glycoprotein GPIIb/IIIa receptors on platelets to aggregate, or clump. Rehabilitation/Physical Therapy must begin early after stroke, however, they cannot change the brain damage. The goal of rehabilitation is to improve function so that the stroke survivor can become as independent as possible.
Although some of the acute treatments showed promise in clinical trials, a study conducted in Cleveland showed that only 1.8% of patients presenting with stroke symptoms even received the t-PA treatment (Katzan IL, et al., 2000 JAMA, 283:1151-1158). t-PA is currently the most widely used of the above-mentioned acute stroke treatments, however, the number of patients receiving any new “effective” acute stroke treatment is estimated to be under 10%. These statistics show a clear need for the availability of acute stroke treatment at greater than 24 hours post stroke.
For some of these acute treatments (i.e., t-PA) the time of administration is crucial. Recent studies have found that the average time of arrival at the hospital is between 3 and 6 hours after stroke (Evenson et al., 2001 Neuroepidemiology, 20(2):65-76.) t-PA has been shown to enhance recovery of ˜⅓ of the patients that receive the therapy, however a recent study mandated by the FDA (Albers et al., 2000 JAMA, 283(9):1145-50.) found that about a third of the time the three-hour treatment window was violated resulting in an ineffective treatment. With the exception of rehabilitation, the remaining acute treatments are still in clinical trials and are not widely available in the U.S., particularly in rural areas, which may not have large medical centers with the needed neurology specialists and emergency room staffing, access to any of these new methods of stroke diagnosis and therapy may be limited for some time.
The cost of stroke in the US is over $43 billion, including both direct and indirect costs. The direct costs account for about 60% of the total amount and include hospital stays, physicians' fees, and rehabilitation. These costs normally reach $15,000/patient in the first three months; however, in approximately 10% of the cases, the costs are in excess of $35,000. Indirect costs account for the remaining portion and include lost productivity of the stroke victim, and lost productivity of family member caregivers.
Approximately 750,000 strokes occur in the U.S. every year, of which about ⅓ are fatal. Of the remaining patients, approximately ⅓ is impaired mildly, ⅓ is impaired moderately, and ⅓ is impaired severely. Ischemic stroke accounts for 80% of these strokes.
As the baby-boomers age, the total number of strokes is projected to increase substantially. The risk of stroke increases with age. After age 55, the risk of having a stroke doubles every decade, with approximately 40% of individuals in their 80's having strokes. Also, the risk of having a second stroke increases over time. The risk of having a second stroke is 25-40% five years after the first. With the over-65 portion of the population expected to increase as the baby boomers reach their golden years, the size of this market will grow substantially. Also, the demand for an effective treatment will increase dramatically.
Given the inability to effectively mitigate the devastating effects of stroke, it is imperative that novel therapeutic strategies are developed to both minimize the initial neural trauma as well as repair the damage brain once the pathological cascade of stroke has run its course.
Transplantation of stem cells has been proposed as a means of treating stroke. Neural stem cells are important treatment candidates for stroke and other CNS diseases because of their ability to differentiate in vitro and in vivo into neurons, astrocytes and oligodendrocytes. The powerful multipotent potential of stem cells may make it possible to effectively treat diseases or injuries with complicated disruptions in neural circuitry, such as stroke where more than one cell population is affected.
Despite this great potential, an easily obtainable, abundant, safe, and clinically proven source of stem cells has been elusive until recently. Umbilical cord blood contains a relatively high percentage of hematopoietic stem cells capable of differentiating into all of the major cellular phenotypes of the CNS, including neurons, oligodendrocytes, and glial cells (Sanchez-Ramos et al., 2001 Exp Neurol., 171(1):109-15; Bicknese et al., 2002 Cell Transplant, 11(3):261-4). Following intravenous delivery, human umbilical cord blood (HUCB) cells survive and migrate into the CNS of normal and diseased animals and have been shown to promote functional recovery in animal models of stroke, spinal cord injury, and hemorrhage (Chen et al., 2001 Stroke, 32(11):2682-8; Lu et al., 2002 Cell Transplant, 11(3):275-81; Saporta et al., 2003 J. Hematotherapy & Stem Cell Research, 12:271-278).
In addition to the growing body of evidence supporting the neurotherapeutic potential of HUCB cells, there is a long and well-established series of practical advantages of using HUCB for clinical diseases. Cord blood is easily obtained with no risks to the mother or child. A blood sample is taken from the umbilical vein attached to the placenta after birth. The percentage of the primitive stem cells present in the mononuclear fraction is small, but the absolute yield of stem cells available may number in the thousands prior to expansion or other ex vivo manipulation, providing an easily obtainable and plentiful source. Hematopoietic stem cells from HUCB have been routinely and safely used to reconstitute bone marrow and blood cell lineages in children with malignant and nonmalignant diseases after treatment with myeloablative doses of chemoradiotherapy (Lu et al., 1996 Crit Rev Oncol Hematol., 22(2):61-78; Broxmeyer, Cellular characteristics of cord blood and cord blood transplantation., in AABB Press. 1998: Bethesda). Early results indicate that a single cord blood sample provides enough hematopoietic stem cells to provide both short- and long-term engraftment. This suggests that these stem cells maintain extensive replicative capacity, which may not be true of hematopoietic stem cells obtained from the adult bone marrow.
In addition, HUCB cells can also be easily cryopreserved following isolation. Cryopreservation of HUCB cells, accompanied by sustained good cell viability after thawing, also allows long-term storage and efficient shipment of cells from the laboratory to the clinic. Thus, this novel feature of cryopreservation gives HUCB a commercially distinct advantage in the design of cell-based therapeutic products. Although the duration of time that the cells may be stored with high viability upon thawing remains to be determined, it has been reported that HUCB cells may be frozen for at least 15 years, viable cells thawed, and transplanted within animal models of injury (Broxmeyer et al., 2003 Proc Natl Acad Sci USA., 100(2):645-650).
Because HUCB transplant recipients exhibit a low incidence and severity of graft-versus-host disease (Wagner et al., 1992 Blood, 79(7):1874-81; Gluckman et al., 1997 N Engl J. Med., 337(6): 373-81), long-term immune suppression with its associated health risks may be unnecessary, making HUCB an ideal candidate for cell-based products. Furthermore, as the technology for banking cord blood stem cells improves, it is possible that autologous transplantation (i.e., transplantation of an individual's own cells back into the body) will be plausible. This would completely eliminate the need for immune suppression during cellular therapy.
Intravenously administered HUCB cells preferentially survive and differentiate into neurons in the damaged brain, and promote behavioral recovery in preclinical models of stroke. While intravenous delivery of HUCB cells clearly promotes functional recovery in pre-clinical models of stroke, the behavioral improvements are only partial, leaving significant room for increments in the efficacy of these cells.
It has been previously recognized that the blood-brain barrier regulates entry of many blood-borne substances into the brain, and may exclude potentially therapeutic agents from entering the brain. Recently, Cornford & Cornford proposed that large neurotherapeutic molecules can be conjugated to peptidomimetic ligands, which bind to selected peptide receptors and are internalized in pinocytotic vesicles and thus cross the blood-brain barrier (Cornford & Cornford, 2002 Lancet Neurol., 1(5):306-15.) Others have proposed endovascular restorative neurosurgery as a novel method of inserting therapeutic agents into the brain, which avoids a craniotomy and allows the therapeutic agent to cross the blood brain barrier (Amar et al., 2003 Neurosurgery, 52(2):402-12). The transvascular route of delivery to the brain allows for the therapeutic molecules to cross the blood-brain barrier, and allows for widespread drug delivery to the brain (Pardridge, 2002 Neuron, 36(4):555-8). Alternatively, the blood-brain barrier can be completely avoided by inserting cellular implants into the CNS area of interest whereby the implant produces and releases therapeutic molecules directly into the CNS, such as by the encapsulation and insertion of xenogeneic cells within a selectively permeable polymeric membrane (Emerich & Winn, 2001 Crit Rev Ther Drug Carrier Syst., 18(3):265-98; Emerich & Salzberg, 2001 Cell Transplant, 10(1):3-24). However, none of these methods adequately addresses enhancing the neuroprotective effects observed with umbilical cord blood cells.
Because of the difficulty in effectively treating patients with neurological disorders, especially using cell-based therapies, there is a need in the art for methods and compositions to enhance the treatment of modalities.